Therapeutic derivatives of diphosphonates
Novel chemotherapeutic agents having utility in treating infectious diseases such as periodontal disease, certain urinary tract infections, infectious urinary tract stones, and bone cancer, are obtained by combining chemically a diphosphonate compound with a therapeutic agent effective against the foregoing diseases.
Claims
1. A method for preparing a compound of the formula A--(V).sub.m --(R).sub.n --Z, wherein A is the residue of a pharmaceutically active antibiotic chemical entity, V is O, S, NR', CONR', CO--O, O--CO, O--CO--O, CO--S, S--CO, S--CO--S, NR'--CO, OCO--NR', NR'--CO--O, NR'--CO--NR", CO--NR", CO--NR'--NR", NR'--NR"--CO, NR'--C(.dbd.NH)--NR" or NR'--C(.dbd.NH)--NH--C(.dbd.NH)--NR" wherein R, R' and R" are H or an organic or heteroorganic group, and m and n are each 1, or one of m and n is 0,
- comprising reacting a pharmaceutically active antibiotic entity of the formula A--V' wherein V' is halogen, OH, SH, NR'R", COOR', CO--X wherein X is halogen or azido, O--CO--X wherein X is halogen, O--CO--OR', CO--SR', S--CO--X, NR'--CO--X, NR'--NHR", NR'--CN, NR'--C(.dbd.NH)--NH--CN, or metal (covalently bound or ionic),
- with a diphosphonate compound of the formula V'--R--Z wherein V' and R have the previous meanings and Z is ##STR10## which optionally may be protected, the composition of V' in the pharmaceutically active chemical entity of formula A--V' and in the diphosphonate compound of formula V'--R--Z being different and being selected to permit a condensation reaction therebetween.
2. A method for preparing a compound of claim 1 of the formula A--Z, comprising subjecting a compound of formula A--V', wherein A and Z have the same meaning as in claim 1, and V' is COOH, to conditions effective to convert the COOH group to Z.
3. A method according to claim 1 wherein V is NH, said compound being formed from a pharmaceutically active chemical entity wherein V' is halogen, amino, or a sulfonate ester, and a diphosphonate compound wherein V' is amino or halogen.
4. A method according to claim 1 wherein V is a tertiary amino-containing group, said compound being formed from a pharmaceutically active chemical entity wherein V' is halogen, a sulfonate ester or a secondary amino-containing group, and a diphosphonate compound wherein V' is a secondary amino-containing group or halogen.
5. A method according to claim 1 wherein V is CONR', said compound being formed from a pharmaceutically active chemical entity wherein V' is carboxyl, and a diphosphonate compound wherein V' is primary or secondary amino.
6. A method according to claim 1 wherein V is NR'CO, said compound being formed from a pharmaceutically active chemical entity wherein V' is primary or secondary amino, and a diphosphonate compound wherein V' is carboxyl.
7. A method according to claim 1 wherein V is CO--O, said compound being formed from a pharmaceutically active chemical entity wherein V' is carboxyl or a reactive carboxyl group derivative, and a diphosphonate compound wherein V' is halogen or hydroxyl.
8. A method according to claim 1 wherein V is O--CO, said compound being formed from a pharmaceutically active chemical entity wherein V' is halogen or hydroxyl, and a diphosphonate compound wherein V' is carboxyl.
9. A compound of the formula A--(V).sub.m --(R).sub.n --Z, wherein A, V, R, and Z have the same meaning as in claim 1, and m and n are independently 0 or 1.
11. A composition comprising a pharmaceutically effective amount of a compound of claim 9 and a pharmaceutically acceptable carrier.
12. A method of treating diseases selected from the group consisting of osteomyelitis, periodontal disease, urinary tract infections, infectious urinary tract stones, and bone cancer, comprising administering a compound of claim 9 in an amount effective to treat said disease.
13. A compound of claim 9 wherein A is the residue of a pharmaceutically active antibiotic compound selected fron the group consisting of an aminoglycoside, an amphenicol, an ansamycin, a.beta.-lactam, a diaminopyrimidine, a lincosamide, a macrolide, a monobactam, a nitrofuran, an oxacephem, a polypeptide, a quinolone, a quinolone analog, a sulfonamide, a sulfone and a tetracycline.
14. A compound of claim 9 wherein V is O, S, NR', CONR', CO--O, O--CO, O--CO--O, CO--S, S--CO, S--CO--S, NR'--CO, OCO--NR', NR'--CO--O, NR'--CO--NR", CO--NR'--NR", NR'--NR"--CO, NR'--C(.dbd.NH)--NR" or NR'--C(.dbd.NH)--NH--C(.dbd.NH)--NR".
15. A compound according to claim 14 wherein V is NR', CONR', OCO--NR', NR'--CO--NR", CO--NR'--NR", NR--C(.dbd.NH)--NR" or NR'--C(.dbd.NH)--NH--C(.dbd.NH)--NR".
16. A compound according to claim 14 wherein V is CO--O, O--CO, O--CO--O, S--CO, NR'--CO, NR'--CO--O, or NR'--NR"--CO.
17. A compound according to claim 14 wherein V is O, S, CO--S or S--CO--S.
19. A compound of claim 13 wherein the.beta.-lactam is selected from the group consisting of carbapenems, cephalosporins, cephamycins, and penicillins.
20. A compound of claim 9 wherein in any individual compound only one of the following conditions exist:
- (a) both m and n are 0,
- (b) both m and n are 1, or
- (c) one of m and n is 1 and the other is 0.
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Type: Grant
Filed: Jun 7, 1995
Date of Patent: Dec 29, 1998
Inventors: John F. Hartmann (Princeton Junction, NJ), Dan Farcasiu (Pittsburgh, PA)
Primary Examiner: Matthew V. Grumbling
Attorney: Donald J. Perrella
Application Number: 8/473,787
International Classification: A61K 3143; A61K 31545; A61K 31495; C07F 902;